Project Summary/Abstract Fibroblast growth factor 21 (FGF21) is a hormone that is induced by various metabolic stresses that regulate energy homeostasis. In addition to being expressed in liver and neurons, FGF21 crosses the blood-brain barrier and exerts many of its actions by acting on its receptor in the central nervous system (CNS). FGF21 acts through a conventional FGF tyrosine kinase receptor in complex with ?-Klotho (KLB), a single-pass transmembrane protein whose restrictive expression pattern directs FGF21 tissue specificity. Transgenic mice, expressing high levels of FGF21, showed a decrease in alcohol preference in comparison to wild-type (WT) mice. KLB knockout (KO) mice had an increased alcohol preference. In humans, the KLB gene SNP rs11940694 is associated with a reduction in alcohol drinking. Mice administered FGF21 by osmotic mini-pumps for two weeks showed a decrease in dopamine levels in the nucleus accumbens in comparison to WT mice. FGF21 decreases the preference for alcohol in mice and chronic FGF21 treatment lowers dopamine levels in the nucleus accumbens. This proposal will test the hypothesis that high FGF21 levels and FGF21 signaling through its CNS receptor will reduce morphine reward in mice and that inhibition of FGF21 signaling will increase the preference for morphine. Also, this proposal will test the hypothesis that high FGF21 levels will attenuate the development of morphine analgesic tolerance and dependence. FGF21 activates some kinases and phospholipases that have been implicated in opioid tolerance development. The Specific Aims of this proposal are 1) to determine if high FGF21 levels decrease the preference for morphine in the conditioned place preference (CPP) paradigm. FGF21-Tg mice and wild-type mice administered the HDAC inhibitor trichostatin A to upregulate FGF21 levels and the stable FGF21 analog PF- 05231023 to increase signaling through the FGF21 receptor, will be tested for morphine preference; 2) to determine if mice lacking the FGF21 co-receptor KLB, and therefore, lacking FGF21 signaling, respond differently than WT mice to morphine in the CPP, and 3) to determine if high FGF21 levels and FGF21 signaling alter morphine analgesia, tolerance and dependence. This proposal is appropriate for CEBRA funding because novel hypotheses will be tested, which if confirmed, the results would have a substantial impact on our understanding of the role of FGF21 in the rewarding properties of morphine and in mediating morphine-induced antinociception and tolerance. FGF21 and its receptor may be novel therapeutic targets for treating opioid dependence.